There is a high co-morbidity between alcohol and nicotine dependence. Alcohol-dependent smokers show an increased risk of tobacco-related mortality and morbidity, and smoking-related illnesses are the leading cause of death among alcoholics. Therefore, there is a crucial need to consider smoking when we treat alcoholics. Currently, there are no approved medications able to reduce both alcohol drinking and smoking in individuals with alcohol and nicotine co-dependencies. Therefore, there is a critical need in the field to identify medications that may be effective in treating both dependencies. Recent research evidence suggests the involvement of the GABAB receptor in the neurobiology of addictions. Human studies have shown that the selective GABAB receptor agonist baclofen reduces alcohol craving and intake. Interestingly, baclofen showed efficacy and a safe profile even when administered to a severely ill population - alcohol dependent patients with cirrhosis. Moreover, a recent double-blind placebo- controlled trial in non-alcoholics also indicated that baclofen reduced the number of cigarettes smoked per day and cigarette craving, suggesting the utility of baclofen in smoking cessation. These results lead one to conclude that baclofen has the potential to be a new pharmacotherapy intervention for the treatment of alcohol dependent patients who smoke, though this aspect has never been formally investigated. Based on this background, Dr. Leggio received a grant from the 'ABMRF/The Foundation for Alcohol Research'to perform a 12-week double-blind, placebo-controlled between-subject treatment study to investigate the dual roles of baclofen (80mg/d) in reducing alcohol and cigarette consumption in alcohol- dependent, heavy-drinking individuals who also satisfy DSM-IV criteria for current nicotine dependence. The primary aims of that study are to investigate whether baclofen, as compared to placebo, reduces the percentage of heavy drinking days and increases alcohol abstinence (cumulative alcohol abstinence duration);and whether baclofen, as compared to placebo, reduces the number of cigarettes per day and increases smoking abstinence (cumulative smoking abstinence duration). The present proposal is consistent with the goals of the present RFA SOAR-R03 to supplement new investigators/early stage investigators who have a commitment of support to conduct research in clinical alcohol research from funding sources other than NIH (e.g. private foundation). The present R03 SOAR consists of a sub-study, which will allow adding a laboratory biobehavioral component to the parent ABMRF- funded study. While the parent funded study will compare the efficacy of baclofen to placebo on alcohol and cigarette consumption during a 12-week naturalistic period, the goal of the present R03 SOAR is to provide information on the biobehavioral mechanisms of how baclofen affects urges to drink and smoke after exposure to nonalcoholic (neutral) vs. alcoholic cues. Specifically, this R03 SOAR sub-study project will be a 1-day double-blind, placebo-controlled, between-subject randomized cue-reactivity (CR) experiment with baclofen (80mg/d) conducted in those alcohol-dependent nicotine-dependent participants of the parent study. During the experiment, urges to drink and to smoke will be assessed after exposure to nonalcoholic and alcoholic cues. Attention to the sight and smell of cues and psychophysiological responses (heart rate, mean arterial pressure and salivation changes) will also be assessed during the CR experiment. The overall goal of this experiment is to explore the biobehavioral mechanisms how baclofen affects urges to drink and smoke after the exposure to alcoholic cues. PUBLIC HEALTH RELEVANCE: Alcohol use disorders account for 100,000 excess deaths per year. Alcohol-dependent smokers show an increased risk of tobacco-related mortality and morbidity, and smoking-related illnesses represent the leading cause of death among alcoholics. Interventions that reduce both alcohol and nicotine dependence may have important public health implications. The goal of this research is to explore the biobehavioral mechanisms of how baclofen affects urges to drink and smoke in alcoholic smokers. This gain in knowledge may lead to more effective pharmacological treatments for alcoholic smokers.